The role of hepatic microsomal mixed function oxidase metabolism in potentiating the toxicity of fluorinated ether anesthetics will be investigated. The anesthetic fluroxene and a group of similar compounds will be used in studies with rats to determine the mechanism whereby these anesthetics exhibit toxic effects. Investigations of the in vitro metabolism of the anesthetics will be performed with variously induced hepatic microsomal preparations and with reconstituted systems containing various forms of purified cytochrome P-450 and NADPH cytochrome P-450 reductase. The effects of cytochrome P-450 inhibitors on the metabolism will also be studied. The results of these studies will be correlated with earlier results on the effects of these anesthetics in rats pretreated with cytochrome P-450 inducing agents. Blood levels of anesthetic and metabolites and exhalation rates will be determined following administration of a single dose of anesthetic i.p., and the results will be correlated with the in vitro results. Serum glutamate-pyruvate transaminase activities in the rats will be determined at various time periods after administration of anesthetic to relate liver damage with other toxic effects of the anesthetics. These toxic effects include mortality and destruction of cytochrome P-450. The mutagenicity of fluroxene and analogous compounds will be tested using the bacterial reversion assay of Ames. Variously induced rat liver microsomes will be used in the assay in an effort to elucidate the role of specific forms of cytochrome P-450 in the generation of activated metabolites of the anesthetics. The results will be utilized in the design of safer and more effective anesthetics, and will facilitate development of an understanding of the toxicity of chemically similar environmental pollutants.